Abstract
MicroRNAs play important roles in many biological processes. Their aberrant expression can have oncogenic or tumor suppressor function directly participating to carcinogenesis, malignant transformation, invasiveness and metastasis. Indeed, miRNA profiles can distinguish not only between normal and cancerous tissue but they can also successfully classify different subtypes of a particular cancer. Here, we focus on a particular class of transcripts encoding polycistronic miRNA genes that yields multiple miRNA components. We describe ‘clustered MiRNA Master Regulator Analysis (ClustMMRA)’, a fully redesigned release of the MMRA computational pipeline (MiRNA Master Regulator Analysis), developed to search for clustered miRNAs potentially driving cancer molecular subtyping. Genomically clustered miRNAs are frequently co-expressed to target different components of pro-tumorigenic signaling pathways. By applying ClustMMRA to breast cancer patient data, we identified key miRNA clusters driving the phenotype of different tumor subgroups. The pipeline was applied to two independent breast cancer datasets, providing statistically concordant results between the two analyses. We validated in cell lines the miR-199/miR-214 as a novel cluster of miRNAs promoting the triple negative breast cancer (TNBC) phenotype through its control of proliferation and EMT.
Highlights
MicroRNAs are small RNA molecules emerged as important regulators of gene expression at the posttranscriptional level
Two independent datasets were used, a first paired miRNA/mRNA expression dataset from a in-house cohort of 129 breast carcinoma tumour samples (which we refer to as Curie dataset [53,54] and a second dataset from The Cancer Genome Atlas project composed of 397 samples [55]
Expression data required for running ClustMMRA were pre-processed as described in Methods and the signatures for breast cancer subtypes were defined using the approach proposed in [34]
Summary
MicroRNAs (miRNAs) are small RNA molecules emerged as important regulators of gene expression at the posttranscriptional level. They have been shown to be involved in the regulation of all essential functions of the cells from differentiation and proliferation to apoptosis [1]. Multiple studies demonstrated the importance of miRNAs in all the cancer hallmarks defined by Hanahan and Weinberg [3] and indicated that they might function as oncogenes or tumor suppressors [4,5,6]. MiRNA profiles can distinguish between normal and cancerous tissue but they can successfully classify different subtypes of a particular cancer [8,9], notably of breast cancer [10,11,12]
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